Mendelian susceptibility to mycobacterial disease (MSMD) is a primary immunodeficiency syndrome characterized by severe disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy patients. Patients with MSMD are also vulnerable to tuberculosis and salmonellosis, though other infections are rare. First described clinically in the 1950s, the pathogenesis of MSMD remained unclear until 1996, when its first genetic etiology was deciphered in children with interferon-y receptor 1 (IFN-yRI) deficiency. Genetic dissection of MSMD over the last 18 years has identified 9 morbid genes, including 7 autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8, ISG15) and 2 X-linked (NEMO, CYBB) genes. The high level of allelic heterogeneity at these loci has led to the definition of 18 distinct disorders. The pathogenesis of MSMD in patients with these disorders involves impaired interleukin-12 (IL-12)-dependent IFN-y immunity. However, only about half of the 700 patients tested in our lab carried any of these genetic defects. We hypothesize that MSMD in other patients results from other monogenic inborn errors of immunity, possibly but not necessarily involving the I L - 1 2 - I F N - Y circuit. We aim to identify new MSMD-causing genes by following a hypothesis-free, genome-wide (GW) approaches, based on X-linked mapping for defects in X-linked genes, homozygosity mapping for defects in autosomal genes, and whole-exome sequencing (WES) for other novel MSMD-causing defects. Our discoveries neatly illustrate the power of GW approaches, particularly WES. From a basic biological standpoint, this research will provide considerable and novel insights into the mechanisms of immunity to mycobacteria. Elucidation of the molecular genetic basis of MSMD will also shed light on the pathogenesis of mycobacterial disease, making it possible to provide molecular diagnoses for patients and genetic counseling for families. This new information will pave the way for the use of IFN-y or other cytokines for the treatment of mycobacterial diseases, in addition to antibiotics. Finally, the genetic dissection of MSMD will pave the way for the genetic dissection of severe tuberculosis in otherwise healthy children. RELEVANCE (See instructions): The known genetic etiologies of Mendelian susceptibility to mycobacterial disease (MSMD) impair interferon (IFN)-v-mediated immunity. Nearly half the patients with MSMD lack a genetic etiology. We hypothesize that MSMD in these patients also results from inborn errors of immunity, which we aim to identify using hypothesis-free, GW approaches.